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Comments on Primary Papers and News

A sizable proportion of elderly individuals with substantial AD pathology does not appear to progress to dementia, indicating that specific neuroprotective mechanisms must exist to evade progressive cognitive decline. The elegant and comprehensive study by Lu et al. provides convincing evidence that the developmental transcriptional factor REST, together with epigenetic repression of REST target genes, regulates a neuroprotective stress response that appears to be essential for proper neuronal functions and cognitive preservation during aging. The authors demonstrate that REST is induced in specific neuronal populations of the aging human brain to confer oxidative stress resistance and protection against toxic insults associated with aging and AD. Intriguingly, in individuals who met pathological criteria for AD, nuclear REST was significantly elevated in cognitively preserved, as compared to cognitively impaired, subjects, suggesting that failure of the brain’s cellular stress response system underlies the transition from successful to pathological brain aging.

These exciting findings provide a molecular signature of a crucial stress-response program that will certainly advance the field toward the identification and further characterization of neuroprotective signaling pathways with highest therapeutic relevance for AD and other aging-associated neurodegenerative diseases. Besides oxidative stressors, the authors identified Wnt-β-catenin signaling as an inducer of REST in the aging brain. It will be highly relevant to see whether other neurodevelopmental programs that are maintained in the adult brain to sustain synaptic plasticity and cognitive functions are also involved in maintaining REST-mediated signaling in the aging brain.

There are a number of puzzling aspects of the manuscript from the Yankner lab and the comments provided by different reviewers. The most remarkable is the lack of any citation, either by the authors of the manuscript, or any of the commentators, of earlier studies that show REST to be activated in adult neurons by ischemia (Calderone et al., 2003; Noh et al., 2012). How come? If these findings are thought to be suspect, the authors should explain why. If not they probably explain why aging brains express REST. In any case it is premature to label REST a “protective factor”, so far it is at best correlative. There are many uncertainties that remain to be explored.